As the majority of small molecule drugs (and drug candidates) targeting the CMS are heterocycles, predominantly nitrogen heterocycles, the focus of our NS program is the invention of new chemistry for preparing heterocycles. A unique aspect of this program is our invention and development of new chemical transformations that use cyclization and rearrangement cascades of charged intermediates to quickly assemble nitrogen and oxygen heterocycles having high constitutional and stereochemical complexity. If the aims of this application are realized, biomedical researchers will have new tools for preparing and modifying the structure of complex nitrogen and oxygen heterocycles. The availability of the new organic synthesis methods that we are developing will facilitate discovery and production of improved chemical agents for treating a variety of medical disorders. An integrated set of exploratory and total synthesis investigations are proposed that will further expand the scope of the Prins-pinacol synthesis of polycyclic ethers and the aza-Cope-Mannich synthesis of polycyclic amines. The natural products targeted for total synthesis - daphnipaxinin, sieboldine A, asbestinin-17, aspergillin PZ, and 1,5-epoxysalvial-4(14)-ene - have not been previously prepared, so our investigations will define synthetic strategies for assembling these uncommon, bioactive, structural motifs. The proposed studies will define the chemical peculiarities of these target molecules, develop chemistry for manipulating their structures, and provide analog structures for biological evaluation. Daphniphyllum alkaloids are neurotoxic and target directly the central nervous system, resulting in depression of voluntary movement as well as respiratory function; daphnipaxinin was isolated form an evergreen tree whose leaves and stems are used as antiinflammation herbs in Chinese folk medicine. Sieboldine A is an acetylcholinesterase inhibitor, comparable in effectiveness to (+/-)-huperazine. The asbestinin class of cembrane-derived marine natural products exhibit not only strong antitumor and antimicrobial activities, but also acetylcholine and histamine antagonism. The fungal metabolite, Aspergillin PZ, is reported to induce strong morphological deformation of P. oryzae at 90 nM, suggesting potential antitumor activity. Because of the scarcity of these natural products from their natural sources, little biological evaluation has been carried out.